PMID- 38054640
OWN - NLM
STAT- MEDLINE
DCOM- 20240112
LR  - 20240112
IS  - 1479-6813 (Electronic)
IS  - 0952-5041 (Linking)
VI  - 72
IP  - 2
DP  - 2024 Feb 1
TI  - Oxidative and ER stress by elevated insulin biosynthesis and palmitic acid in 
      insulin-producing cells.
LID - e230087 [pii]
LID - 10.1530/JME-23-0087 [doi]
AB  - The early phase of type 2 diabetes mellitus (T2DM) is characterised by insulin 
      resistance, which can initially be compensated by elevated insulin secretion. 
      However, as postulated by the workload hypothesis, over time harming insulin 
      requirements contribute to beta-cell dysfunction and death. The mechanisms behind 
      this transition are complex and not fully understood but involve factors such as 
      endoplasmic reticulum (ER) stress raised by gluco/lipotoxicity. To investigate 
      the effect of excessive insulin folding on ER luminal H2O2 generation, ER stress 
      and viability, insulin was expressed glucose-independently by a 
      doxycycline-regulated Tet-On system in insulin-producing RINm5F cells. 
      Additionally, the effect of palmitic acid (PA) as a subsidiary T2DM-associated 
      factor was examined in this model system. Elevated insulin expression increased 
      ER luminal H2O2 concentration quantified by the fluorescent sensor protein TriPer 
      and reduced viability, but did not activate apoptosis. However, when combined 
      with PA, insulin expression resulted in a significant increase in ER stress and 
      apoptosis. Expression of ER-localised catalase verified the specificity of the 
      applied H2O2 detection method without attenuating ER stress, caspase activation 
      or viability loss. These findings suggest that hyperinsulinism alone can cause 
      increased ER luminal H2O2 generation, mild ER stress and reduced viability, while 
      hyperinsulinism in combination with PA accelerates these processes and triggers 
      apoptosis. The inability of ER catalase to counteract these effects suggests that 
      further damaging factors besides H2O2 are involved in cell dysfunction. Finally, 
      reducing the high insulin demand in the initial phase of T2DM may be crucial in 
      preventing further beta-cell damage caused by gluco/lipotoxicity.
FAU - Vidrio-Huerta, Brenda
AU  - Vidrio-Huerta B
AD  - Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
FAU - Plotz, Thomas
AU  - Plotz T
AD  - Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
FAU - Lortz, Stephan
AU  - Lortz S
AUID- ORCID: 0000-0002-3392-8978
AD  - Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
LA  - eng
PT  - Journal Article
DEP - 20240111
PL  - England
TA  - J Mol Endocrinol
JT  - Journal of molecular endocrinology
JID - 8902617
RN  - 2V16EO95H1 (Palmitic Acid)
RN  - EC 1.11.1.6 (Catalase)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - 0 (Insulin)
SB  - IM
MH  - Humans
MH  - Palmitic Acid/pharmacology
MH  - Catalase/metabolism/pharmacology
MH  - *Diabetes Mellitus, Type 2/metabolism
MH  - Hydrogen Peroxide/pharmacology
MH  - *Insulin-Secreting Cells/metabolism
MH  - Insulin/metabolism
MH  - Apoptosis
MH  - *Insulin Resistance
MH  - Oxidative Stress
MH  - Endoplasmic Reticulum Stress
OTO - NOTNLM
OT  - catalase
OT  - endoplasmic reticulum
OT  - gluco-lipotoxicity
OT  - insulin-secreting cells
OT  - palmitic acid
OT  - protein folding
OT  - reactive oxygen species
EDAT- 2023/12/06 12:43
MHDA- 2024/01/12 06:43
CRDT- 2023/12/06 08:42
PHST- 2023/11/02 00:00 [received]
PHST- 2023/12/06 00:00 [accepted]
PHST- 2024/01/12 06:43 [medline]
PHST- 2023/12/06 12:43 [pubmed]
PHST- 2023/12/06 08:42 [entrez]
AID - JME-23-0087 [pii]
AID - 10.1530/JME-23-0087 [doi]
PST - epublish
SO  - J Mol Endocrinol. 2024 Jan 11;72(2):e230087. doi: 10.1530/JME-23-0087. Print 2024 
      Feb 1.